A 1-week intradermal dose-sparing regimen for rabies post-exposure prophylaxis (RESIST-2): an observational cohort study.

BACKGROUND: The international health authorities are backing an effort to eliminate canine-mediated rabies in humans by 2030. This effort will require improving access to adequate and timely rabies post-exposure prophylaxis as compliance is low with WHO-recommended regimens (given in four to five visits over 1 month). Access could be substantially improved by an abridged regimen to reduce doses, direct and indirect costs, and improve vaccine equity by better sharing of available vaccine. We aimed to compare rabies virus neutralising antibody titres before and after the fourth visit to determine whether that session was needed or the current regimen could be abridged. METHODS: In this observational cohort study, we measured rabies virus neutralising antibody titres using rapid fluorescent focus inhibition tests in 116 people bitten by dogs with laboratory-confirmed rabies and 20 control individuals. Percentages of circulating plasmablasts were determined by flow cytometry. All individuals had been referred to the rabies prevention clinic at Institut Pasteur in Cambodia and received two intradermal injections of post-exposure prophylaxis on days 0, 3, 7, and 28 (Thai Red Cross regimen) with or without equine rabies immunoglobulin, as per 2010 WHO recommendations. FINDINGS: All individuals had rabies virus neutralising antibody titres considered protective (≥0·5 IU/mL) and plasmablast activation on day 28 before the last injection. The median rabies virus neutralising antibody concentration in the group of individuals bitten by rabies virus-positive dogs was 1·08 IU/mL (IQR 0·37-3·09) on day 7, 26·86 (22·68-49·50) on day 28, and 26·74 (11·78-49·06) on day 42. No significant differences were observed in titres between days 28 and 42, after titres reached a plateau. These titres were reached notwithstanding equine rabies immunoglobulin use, age, sex, nutrition status as indicated by upper-arm circumference in children or BMI in adults, or dog infection status. Titres or plasmablast percentages did not increase between the day of the last injection and 2 weeks later. All patients were alive 1 year after post-exposure prophylaxis. INTERPRETATION: The fourth vaccine session on day 28 provides no additional benefit. Rabies post-exposure prophylaxis can be abridged to a two-dose, three-session, 1 week regimen to improve post-exposure prophylaxis coverage and equity at no risk to patients. FUNDING: Institut Pasteur.

[Tuberculosis and HIV co-infection: clinical trial under the coordination of the Institut Pasteur in Cambodia]. / Co-infection tuberculose et VIH: coordination d'un essai clinique randomisé par l'Institut Pasteur du Cambodge.

Tuberculosis is a major cause of death among adults infected by HIV. The CAMELIA (ANRS 1295/CIPRA KH001) randomized clinical trial aimed to determine the optimal timing of ARV initiation after tuberculosis treatment onset to reduce mortality. Here, we describe the trial implementation in five hospitals in Cambodia under the coordination of the Institut Pasteur in Cambodia, its conduct, the challenges and public health benefits in Cambodia and beyond.

Factors associated with negative direct sputum examination in Asian and African HIV-infected patients with tuberculosis (ANRS 1260).

OBJECTIVE: To identify factors associated with negative direct sputum examination among African and Cambodian patients co-infected by Mycobacterium tuberculosis and HIV. DESIGN: Prospective multicenter study (ANRS1260) conducted in Cambodia, Senegal and Central African Republic. METHODS: Univariate and multivariate analyses (logistic regression) were used to identify clinical and radiological features associated with negative direct sputum examination in HIV-infected patients with positive M. tuberculosis culture on Lowenstein-Jensen medium. RESULTS: Between September 2002 and December 2005, 175 co-infected patients were hospitalized with at least one respiratory symptom and pulmonary radiographic anomaly. Acid-fast bacillus (AFB) examination was positive in sputum samples from 110 subjects (63%) and negative in 65 patients (37%). Most patients were at an advanced stage of HIV disease (92% at stage III or IV of the WHO classification) with a median CD4 cell count of 36/mm³. In this context, we found that sputum AFB negativity was more frequent in co-infected subjects with associated respiratory tract infections (OR = 2.8 [95%CI:1.1-7.0]), dyspnea (OR = 2.5 [95%CI:1.1-5.6]), and localized interstitial opacities (OR = 3.1 [95%CI:1.3-7.6]), but was less frequent with CD4 ≤ 50/mm³ (OR = 0.4 [95%CI:0.2-0.90), adenopathies (OR = 0.4 [95%CI:0.2-0.93]) and cavitation (OR = 0.1 [95%CI:0.03-0.6]). CONCLUSIONS: One novel finding of this study is the association between concomitant respiratory tract infection and negative sputum AFB, particularly in Cambodia. This finding suggests that repeating AFB testing in AFB-negative patients should be conducted when broad spectrum antibiotic treatment does not lead to complete recovery from respiratory symptoms. In HIV-infected patients with a CD4 cell count below 50/mm3 without an identified cause of pneumonia, systematic AFB direct sputum examination is justified because of atypical clinical features (without cavitation) and high pulmonary mycobacterial burden.

Anti-tuberculosis drug resistance and HIV co-infection in Phnom Penh, Cambodia.

The objective of this study was to observe the prevalence of drug resistance in Mycobacterium tuberculosis isolates in HIV associated tuberculosis co-infected patients in Phnom Penh City. The isolates of M. tuberculosis were collected during active laboratory-based surveillance. Of the 98 isolates studied, M. tuberculosis resistance to isoniazid was seen in 23.5%, resistance to rifampicin was seen in 16.3% and multidrug-resistance (MDR-TB) was seen in 5.1%. Our findings reveal an alarmingly high level of resistance to isoniazid and rifampicin, and confirms the need for drug susceptibility testing to guide treatment in patients with culture positive tuberculosis.

Predictors of pneumocystosis or tuberculosis in HIV-infected Asian patients with AFB smear-negative sputum pneumonia.

OBJECTIVES: To identify predictors of Pneumocystis jiroveci pneumonia (PCP) or pulmonary tuberculosis (TB) in acid-fast bacillus smear-negative HIV-infected patients and to develop clinical prediction rules. DESIGN: A cohort study conducted in consecutive hospitalized Asian patients. METHODS: Multivariate analyses were performed on the Cambodian sample to determine clinical, radiological, and biological predictors of PCP or TB at hospital admission. The Vietnamese sample was kept for independent validation. RESULTS: In Cambodia, the gold standard technique for TB and PCP were fulfilled in 172 (27 cases) and 160 (84 cases) patients, respectively. For TB, independent predictors included the following: headache [odds ratio (OR) 3.0; 95% confidence interval (CI) 1.04 to 8.6], localized radiological opacity (OR 5.8; 95% CI 1.9-17.9), and mediastinal adenopathy (OR 10.1; 95% CI 3.5 to 29.0); and for PCP: resting oxygen saturation <90% (OR 3.3; 95% CI 1.3 to 8.5 for resting arterial oxygen saturation >or=80%; and OR 9.1; 95% CI 1.8 to 44.5 for resting arterial oxygen saturation <80%), trimethoprim-sulphamethoxazole prophylaxis (OR 0.1; 95% CI 0.04 to 0.6), and diffuse radiological shadowing (OR 7.0; 95% CI 2.7 to 18.6). PCP risk predicted by a score based on these 3 factors ranged from 3% to 92% (Cambodia). When tested on Vietnamese patients (n = 69, 38 with PCP), the score maintained correct predictive ability (c-index = 0.72) but with poor calibration. CONCLUSIONS: The PCP score could provide a useful clinical tool to identify PCP among acid-fast bacillus smear-negative pneumonia and start specific therapy.